SUMMARY/ABSTRACT Systemic lupus erythematosus (SLE or lupus) is a deadly and incurable autoimmune disease characterized by widespread inflammation and rampant production of autoantibodies. Clinical disease presents as a heterogeneous spectrum of symptoms and damage to organ systems, including the kidneys and heart. Despite decades of robust insights into the genetic factors contributing to risk for development of SLE, the functional genetic mechanisms governing specific disease manifestations remain undefined. Therefore, accurate disease prognosis and effective prevention of life-threatening organ damage remain challenging. Notably, disease severity and involvement of specific organs in SLE varies amongst different ethnic groups and between disparate strains of inbred mice, strongly suggesting that genetic cues may determine pathogenesis of disease. However, limited genomic variation and restricted recombination rates associated with intercrosses between inbred mouse strains have complicated dissection of these genetic drivers of disease pathogenesis. To better model human disease, the collaborative cross was generated from eight founder strains to capture the tremendous genetic variation present across the mouse genome. The diversity of allele combinations among collaborative cross lines prompts a broader spectrum of disease phenotypes than commonly observed in inbred mice, thereby facilitating high resolution mapping of genetic loci influencing complex polygenic traits. In this proposal, we endeavor to demonstrate that the collaborative cross resource is a powerful tool capable of identifying specific genetic loci linked to clinically important organ-specific manifestations of SLE. We will apply a cutting-edge mouse model of SLE that we find differentially provokes cardiac and renal damage in different inbred mouse strains. The innovative combination of an inducible model of SLE-like disease with the collaborative cross resource will facilitate qualitative and quantitative comparison of disease outcomes among individual strains of mice. The breadth of genetic variation captured in these mice will enable mapping of quantitative trait loci even for small phenotypic variations in disease pathogenesis. This study represents a promising and original approach to address critical, unanswered questions regarding the genetic origins of heterogeneous organ-specific manifestations of SLE. The results of the proposed experiments will open new avenues of basic and translational research into clinically-targetable pathways identified as risk factors for development of life-threatening cardiac and renal pathologies in SLE. Moreover, these results will likely promote additional futures attempts at genetic dissection of other heterogeneous manifestations of SLE, including musculoskeletal, mucocutaneous, neuropsychiatric and pulmonary pathologies.